Resolution of dl-methadone



May 9, 1961 Filed Feb. 18, 1959 H. E. ZAUGG RESOLUTION OF dl-METHADONE 2 Sheets-Sheet 1 May 9, 1961 H. E. ZAUGG RESOLUTION OF dl-METHADONE 2 Sheets-Sheet 2 Filed Feb. 18, 1959 vlllff l/f/IIIIIII;

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United States Patent 6 1 2,983,757 RESOLUTION OF dI-IVIETHADONE Harold E. Zaugg, Lake Forest, 11]., assignor to Abbott Laboratories, North Chicago, 11]., a corporation of ois Filed Feb. 18, 1959, Ser. No. 794,203 4 Claims. (Cl. 260-570) This invention relates to a new method for separating the optical isomers of a racemic composition, in particular til-methadone, and to apparatus for carrying out said method.

It is known that many important chemical compounds occur naturally or are synthesized in the form of a racemic mixture of optical isomers of the composition. Among the better known of such compounds are ephedrine, pantothenic acid, epinephrine, glucose and methadone. Procedures have been worked out for the resolution of the racemic mixture of these chemicals and others wherein the optical isomers are separated by chemical reaction with another compound. This type of procedure is oftentimes unsatisfactory and expensive and to a certain extent has limited the use of the optical isomer. It is also known to place a seed of one of the optical isomers in a solution containing the racemic composition and providing crystal growth on this seed from the corresponding optical isomer in the solution. This procedure is also unsatisfactory because the deposition of the particular optical isomer onto the corresponding seed results in an increased concentration of the remaining isomer in solution, thus enhancing the possibility of the remaining isomer spontaneously crystallizing out of solution onto the seeded crystal. In addition, such a procedure has the further disadvantage of resolving only one isomer for any single operation, and where both optical isomers are desired, tlns necessitates a multiple series of operations.

It is also well known that one of the optical isomers may have properties rendering it many times more useful than the other optical isomers. It is not uncommon in the pharmaceutical field to find that the physiological activity of one isomer is entirely different, both in kind and degree, from the activity of the other isomer. In such case when one is forced to use the racemic mixture because of availability thereof and unavailability of the preferred isomer, he is comprising and accepting a drug which has the average of activity of the better and poorer isomers. A particular example is dl-methadone wherein the laevo isomer possesses marked analgesic activity and the dextro isomer has little or no analgesic activity.

It is a principal object of this invention to provide a new physical method for resolving racemic mixtures of optical isomers, in particular dl-methadone.

Another object of the invention is to provide special apparatus which is ideally suited to the operation of the new physical method of resolution.

A still further object of this invention is to provide a method whereby simultaneous resolution of both optical isomers is attained in optically pure form.

These and other objects and advantages of the invention will become more apparent upon a thorough consideration of the following description of the invention taken in conjunction with the accompanying drawings in which;

Figure 1 is a perspective view of one form of apparatus which is suited for the practice of this invention;

Figure 2 is a cross-sectional view of the apparatus illustrated in Figure 1;

Figure 3 is a cross-sectional view of another form of apparatus suitable for the practice of the invention; and

Figure 4 is a cross-sectional view taken along the lines 4-4 of Figure 3.

. In the accomplishment of the foregoing objects and in accordance with the practice of this invention, there is now provided a method of physically separating optical isomers from a racemic mixture thereof which comprises forming a saturated solution of the racemic mixture, spacing seed crystals of the dextro-rotatory form and the laevo-rotatory form at alternate points at the bottom of the container holding the solution and selectively crystallizing the d-isomer on a d-isomer seed crystal and l-isomer on an l-isomer seed crystal.

The spacing of the seed crystals at the bottom of the container is determined by a minimum distance at which the formed crystals will not overlap as they grow. This will assure discrete crystals of optically pure material. The maximum distance between said seed spacing will be determined by the degree of agitation in the container which will successfully diffuse an optical isomer from an area of greater concentration to an area of lesser concentration without causing spontaneous crystallization by agitating too vigorously.

This critical feature will be better understood by considering the process in greater detail. The dextro and laevo seed crystals are spaced in the bottom of the container holding the saturated solution of the racemic composition. As the dextro isomer comes out of solution onto the dextro seed, a greater concentration of the laevo form occurs. The resulting high concentration of the laevo isomer could lead to spontaneous crystallization of the laevo isomer onto the dextro isomer crystal. This untoward event is circumvented by mildly agitating the racemic solution to diffuse more dextro isomer into this area. The step is directed to effect a homogeneous solution. It will be understood that if the seed crystals are spaced at too great a distance, then the agitation must be more vigorous to attain homogeneity in the solution. The liquid volumes directly above said seed crystals are too far removed to attain said homogeneity with mild agitation. Vigorous agitations will provide homogeneity, but the likelihood of spontaneous crystallization then becomes imminent. This is a result which must be avoided.

It has been accordingly found that the distance between said seeds is 2-5 inches for the operable practice of this process. Seeds spaced within this distance will grow into large crystals without overlapping, thus preserving the optical integrity of any formed crystal. Seeds spaced within this distance will also allow the successful practice of the invention because the agitation within the container will be at a rate which will provide the desired diffusion of the enantiomorphs in solution without causing spontaneous crystallization from excessive agitation.

A cylindrical container of the type illustrated hereinafter provides a mixing element bent at: a point below the level of the liquid so that the resulting radius of eccentricity of the rotating mixing element is approximately one-half of the radius of the cylindrical container. This representative mixing element will provide the desired agitation when it is revolved at a rate of about 230- 260 rotations per minute. The container size is independent of this speed of rotation for it is understood that a container of varying size will have mixing elements providing a corresponding radius of eccentricity as defined heretobefore.

This invention is based on the knowledge that a seed crystal of the dextro-rotatory isomer will attract the d-, isomer in saturated solution, and when the degree of saturation of the solute in the solution is increased, the d-isorner will tend to crystallize out on the d-isomer seed crystal. At the same time, a portion of the l-isomer will tend to crystallize out on the l-isomer seed crystal. This process will continue so long as the solution is supersaturated with the composition or solute and the seeded crystals will grow to substantial size. At the conclusion of the operation it will be found that relatively pure crystals of the d-isomer and l-isomer will have been grown on the seed crystals.

When it is said in this specification that the degree of saturation of the solute in the solvent is increased, it is contemplated that any known form of increasing the degree of saturation may be employed. For example, the solution may be saturated at high temperature and gradually cooled so that the capacity of the solution for dissolving the racemic mixture is reduced according to well-known principles. In another instance, the saturated solution may be evaporated, either at a relatively high temperature, or at lower temperatures by drawing a vacuum over the solution, thereby creating a supersaturated solution from which crystallization occurs. In either of the foregoing instances it will be apparent that a saturated solution may be continually added to the main body of solution in which the solubility of the racemate is being reduced. For example, with continual evaporation from the main body of solution it is possible to feed in a saturated solution of the racemic mixture in order to maintain the volume of the main body substantially constant. The degree of saturation of the solute in solvent may also be increased by adding a different solvent to the solution.

Referring now to the drawings in detail, it will be seen that the apparatus illustrated in Figures 1 and 2 is quite simple in design and is suited for small scale operation of the laboratory type as well as plant scale operation. A container which in this instance is illustrated as being made of glass, but which may be of any non-co rrosive material, has a flange 12 which is adapted to receive a complementary flange 14 which depends from a cover 16. The fasteners 18 are employed to seal the flanges 12 and 14 in substantially air tight position. In the center of the cover 16 there is positioned a sleeve 20 or other suitable equivalent member which is adapted to be joined with the cover 16 and to receive within the bore thereof a shaft 22 which connects a drive motor 24 with the stirring apparatus 26. A packing element (not shown) or equivalent sealing and lubricating means such as a silicone lubricated rubber seal or a quantity of silicone grease may be inserted between the shaft 22 and the bore of the sleeve 20. The stirrer 26 may be made of glass or any other suitable non-corrosive material such as stainless steel, and it desirably is bent at a point somewhat below the average liquid level in the container (as illustrated more clearly in Figure 2) in order that stirring may be accomplished with the minimum of disturbance at the surface of the liquid. The motor 24 has conventional electrical conduits 28 connected to a power source (not shown) and is suitably mounted by means of the bracket 30. A vent 32 having a'valve 34 therein is provided in the'cover 16 in order to regulate evaporation from the container and to provide a conduit for drawing a vacuum on the container 10 if desired. The container may be provided with a jacket (not shown) if desired to provide for heating and cooling of the contents of the container. Other suitable and equivalent heating and cooling means such as a coil may be incorporated into the structure if desired. A conventional thermometer 84 extends through the cover 16 and into the solution 36.

As illustrated in Figures 1 and 2 seed crystals are spaced at the described intervals at the bottom of the container 10. Since it is required to alternate the dextro and laevo crystals, the dextro crystals 38 are illustrated as being located opposite one another in the container and the laevo crystals 40 are spaced at approximately 90 on the circumference with respect to the dextro crystals, andopposite one another. In this particular embodiment, such 90 spacing results in the seeds being separated by about 2 /2 inches along the perimeter of the cylinder, and by about 3 /2 inches along diametric measurement. It will be apparent that several layers of crystals may be positioned in the solution if desired even though only one layer is illustrated herein. A screen or other supporting member (not shown) may be attached to the sides of the container 10, preferably in the form of rings extended inwardly from the side of the container and adapted to receive seed crystals in the same spacial arrangement as defined for crystals 38 and 40 which rest on the bottom of the container.

The form of apparatus shown in Figures 3 and 4 represents another type of apparatus suitable for the operation of the physical resolution process covered by this invention. In these figures a stainless steel or glass-lined vessel 42 is illustrated as having a jacket 44 thereon for heating or cooling the contents of the vessel. Conventional outlets 46 and 48 for the jacket 44 are shown. The vessel 42 has a flange 50 depending therefrom. A similar flange 52 depends from the cover 54 and the flanges are adapted to give a tight fit. An opening in the cover 54 receives a sleeve 56 which in turn receives within the bore thereof a shaft 58. As in the case of the sleeve and shaft of Figures 1 and 2, the sleeve 56 and shaft 58 may be lubricated and sealed by conventional means. The shaft 58 is adapted to reciprocate and is so driven by means of a flexible coupling 60 and ring follower 61 which convert the rotary motion of the eccent ric drive wheel 62 into the reciprocating motion of the shaft 58. The eccentric wheel 62 is connected by the shaft 64 to a gear reducer 66 which in turn is driven by motor 68. The motor is suitably supported by the bracket On the opposite end of the shaft 58 there is positioned one or more perforated discs 70 which provide support for the wire basket 72 upon which the seed crystals 74 are supported during the operation of the process. The shaft 58 and with it the discs 70 and the baskets 72 are adapted to reciprocate vertically within the body of the solution 76, as illustrated by the dotted lines in Figure 3. Again, the cover 54 is equipped with a vent 78 having a valve 80 therein for controlling the evaporation of the solution 76. The vent may also be used as the point of introduction of additional solution if it is desired to operate the apparatus on more or less of a continuous basis. The motor is mounted on a support 82. A thermometer 84, either of the direct reading or recording type, is provided for measuring the temperature of the solution. As illustrated in Figure 3 the thermometer 84 is of the recording type and is connected by the wires 86 to suitable recording apparatus (not shown).

A number of crystals 74 are shown on the basket 72 and it is contemplated that crystals of one of the isomeric forms, such as the dextro form, will be placed on one basket and crystals of the other form, such as the laevo form, will be placed on the adjacent baskets. Hence, in Figure 3 it is contemplated that in one embodiment the crystals 74 will be of the dextro isomer and the crystals 88 will be of the laevo isomer. to arrange crystals of both isomeric forms on the same tray, provided that the two forms are spaced apart as described hereinbefore. The seed crystals are preferably but not necessarily alternated in their spacial relationship.

In one specific embodiment of the method 56 grams of racemic methadone base (6-dimethylamino-4,4-diphenyl-3-heptanone) are dissolved in 225 cc. of boiling petroleum ether (boiling at 6368 C., the particular material being a mixture of petroleum ethers known in the trade as Skellysolve B) and filtered by gravity into a container similar in design to that illustrated in Figure l. The solution is concentrated on a steam bath to a volume of about cc. The cover with stirrer inserted is placed in an oven maintained at 40 C. As the solution cools from near boiling to near 40 C. the stirrer is operated at 240 r.p.m. (it will be apparent that a temperature controlled water bath could be substituted for the oven or a jacketed container could be used. Alternatively, a container fitted with a heating and cooling coilwould also be suitable).

It is possible, of course,

When temperature equilibrium is attained, the cap is removed and two seeds each of pure dextro-methadone base and laevo-methadone base are placed in alternating posltions around the perimeter of the container bottom, so that seeds of like optical rotation are directly opposite each other. The seeds employed here are approximately 23 mm. across and are preferably taken, still wet with solvent, directly out of the petroleum ether solution from which they are freshly crystallized by other known methods. The seeds are separated by about 2 /2 inches along the perimeter and by about 3 /2 inches along the diameter. The cover is replaced and gentle stirring is resumed at the same rate as before and is continued for about 125 hours, holding the solution at about 40 C. During this time approximately one-fourth of the solvent evaporates and two large and two smaller crystals grow from the original seeds. The two crystals of l-methadone weigh 8.8 g. ([a] -35.7; c.=4; Skellysolve B) and 4.2 g. ([a] -|36.O; c.=4; Skellysolve B). The total of 26.1 g. of resolved material represents a 46% yield, but 29.0 g. of dl-methadone is obtained from the residual solution to give nearly a quantitative recovery of product. The observed properties of the crystals correspond very closely to recorded values in the literature.

The embodiments presented herein for practicing the invention present certain critical features and certain descriptive material well within the knowledge and control of the skilled practitioner. The spacing of the seed crystals must be within the foregoing defined distances but the size and shape of the container may be selected to fit the particular needs and designs at hand. The saturated solution of the racemic composition may be maintained by any of the methods well known in the art of which specific illustrations have been presented. The solution can be agitated by any means known in the art. The specific illustrations relating to a rotary mixer and a reciprocating vertical mixer are not intended to be exclusive systems. The degree of agitation within the solution should not be so extreme as to cause splashing of the solution. Such an occurrence increases the possibility of spontaneous crystallization. The teaching of the specification prescribes an agitation which will obtain the desired diffusion but will not result in splashing. This feature of the process may be easily determined by the practitioner for his particular container.

It will be apparent from the foregoing disclosure that the type of solvent employed is not a critical limitation on the invention because the method depends upon increasing the degree of saturation of the chemical (solute) in the solvent, regardless of the actual solubility, provided only that the solvent is inert to the solute; i.e., does not react therewith. Naturally, it will be desirable to use solvents which are reasonably priced and which have a relatively high solvent power for the racemic mixture, but these are only economic considerations. It will also be desirable to employ solvents which are not too difiicult to evaporate, and in this respect, the lower boiling petroleum solvents are well suited.

Crystallization will usually, but not necessarily, be carried out with the solution being maintained at a relatively elevated temperature because at the higher temperatures the solution will hold more of the composition at saturation. Lower temperature conditions may be used but the rate of crystallization will be slower. Naturally, the crystallization will not be carried out at the boiling point of the solution because crystallization will be too rapid. The rate of crystallization will desirably be maintained slow so that most of the crystallization that occurs will be on the seed crystals.

It will be recognized that the seed crystals may be introduced into the solution at any time prior to the onset of crystallization. It will be apparent that the seed crystals should not be introduced at a time when they will completely dissolve before saturation of the solution is reached.

This application is a continuation-in-part of my co- 6 pending application, Serial No. 472,322, filed on December 1, 1954, now abandoned.

It will be recognized that the invention is not limited to the exact form of apparatus nor to the exact mode of operation disclosed herein but rather includes all of the equivalents of apparatus and method which will be suggested to one skilled in the art upon a consideration hereof. All such equivalents are deemed to be a part of this invention provided they fall within the scope of the appended claims.

I claim:

1. The method of separating optical isomers of methadone from a racemic mixture thereof which comprises dissolving dl-methadone in an inert solvent, concentrating said solution to saturation, placing seed crystals of dmethadone and l-methadone within said solution, spacing said seed crystals at a distance of 2-5 inches, increasing the saturation of the solute in the solvent and agitating at a rate sufficient to attain homogeneity without causing spontaneous crystallization, thereby causing selective crystallization of said optical isomers on their respective seed crystals from said solution in a single operation.

2. The method of separating optical isomers of methadone from a racemic mixture thereof which comprises dissolving til-methadone in an inert solvent to saturation, placing seed crystals of l-methadone and d-methadone at a distance of 2-5 inches from one another within said solution, increasing the saturation of the solute in the solvent and agitating at a rate suflicient to attain homogeneity without causing spontaneous crystallization, thereby causing selective crystallization of said optical isomers on their respective seed crystals from said solution in a single operation.

3. A method for separating optical isomers of methadone from a solution of dl-methadone in a substantially cylindrical container having a support within the container at the bottom thereof and a mixing element bent below the level of the solution, which mixing element has a radius eccentricity about one-half of the radius of the cylindrical container, which method comprises dissolving all-methadone in an inert solvent, concentrating said solution to saturation, placing seed crystals of d-methadone and l-methadone in a resting position in the solution, spacing said seed crystals at a distance of 25 inches, increasing the concentration of the ell-methadone in the inert solvent, agitating said solution at a rate sufficient to attain homogeneity without causing spontaneous crystallization, thereby causing selective crystallization of said optical isomers on their respective seed crystals from said solution in a single operation.

4. A method for separating optical isomers of methadone from a solution of til-methadone in a substantially cylindrical container having a support within the container at the bottom thereof and a mixing element bent below the level of the solution, which mixing element has a radius of eccentricity about one-half of the radius of the cylindrical container, said method comprising dissolving til-methadone in a petroleum ether solvent having a boiling point of 63-68 C., concentrating said solution to saturation, placing seed crystals of d-methadone and l-methadone in a resting position in the solution, spacing said crystals at a distance of 2-5 inches, increasing the concentration of the til-methadone in said solvent, agitating said solution at a rate suflicient to attain homogeneity without causing spontaneous crystallization and maintaining the solution temperature at about 40 C., thereby causing selective crystallization of said optical isomers on their respective seed crystals from said solution in a single operation.

Amiard et al. Feb. 14, 1956 Long Oct. 16, 19.56 

1. THE METHOD OF SEPARATING OPTICAL ISOMERS OF METHADONE FROM A RACEMIC MIXTURE THEREOF WHICH COMPRISES DISSOLVING DL-METHADONE IN AN INERT SOLVENT, CONCENTRATING SAID SOLUTION TO SATURATION, PLACING SEED CRYSTALS OF DMETHADONE AND L-METHADONE WITHIN SAID SOLUTION, SPACING SAID SEED CRYSTALS AT A DISTANCE OF 2-5 INCHES, INCREASING 